Combination of l-dopa and 2-imino-5-phenyl-4-oxazolidinone used to treat parkinson{40 s disease

ABSTRACT

Covers a composition comprising the combination of 1-dopa and 2imino-5-phenyl-4-oxazolidinone and salts thereof and use of said composition in treating Parkinson&#39;&#39;s disease.

United States Patent Plotnikoff [451 Aug. 22, 1972 1 COMBINATION OFL-DOPA AND 2- IMINO-5-PHENYL-4-OXAZOLIDINONE USED TO TREAT PARKINSON'SDISEASE [72] Inventor: Nicholas Peter Plotnikoff, Lake Bluff, Ill.

[73] Assignee: Abbott Laboratories, Chicago, Ill.

[22] Filed: Jan. 27, 1971 [21] Appl. No.: 110,253

[52] US. Cl ..424/272, 424/319 51 Int. Cl. ..A61k 27/00 [58] Field ofSearch..; ..424/272, 319

[56] References Cited UNITED STATES PATENTS 3,108,045 10/1963 Candon etal. ,.424/272 OTHER PUBLICATIONS Chem. Abst., Vol. 63, 2279c (1965).

Primary Examiner-Stanley J. Friedman Attorney-Robert L. Niblack [57]ABSTRACT Covers a composition comprising the combination of l-dopa and2-imino-5-phenyl-4-oxazolidinone and salts thereof and use of saidcomposition in treating Parkinsons disease.

4 Claims, No Drawings COMBINATION OF L-DOPA AND 2-IMINO-5-PI-IENYL-4-OXAZOLIDINONE USED TO TREAT PARKINSON'S DISEASE BACKGROUND OFTHE INVENTION Parkinsonism is generally characterized by involuntarytremors, diminished motor power, and rigidity. The onset of the diseaseis insidious, with increasing rigidity or tremor or both. The patientsfacial expression may be fixed or less mobile than normal; smilingspreads and slowly disappears. Body movements generally become slower.There may be gradually increased rigidity with diminished swaying of thearms during walking. Generally, the patients legs may begin to feelstiff and excessive effort may be required to lift them from the groundwhile walking. Patients often assume a stooping posture and shufflerather than walk. As the disease progresses, movements such as adjustinga tie, buttoning a coat, etc., become impossible.

The disease is usually slowly progressive and patients may live for manyyears. However, with increased disability, patients often becomedepressed, anxious, and emotionally disturbed. While treatment withvarious drugs such as antispasmodics, central nervous system stimulantsand the like have been used along or in combination to produce temporaryamelioration of complaints, l-dopa was the first effective single agentin the treatment of the disease.

L-dopa has been reported to be effective against the akinesia andrigidity of Parkinsonism, particularly in extremely severe cases. Anincrease in mental alertness and wakefulness, relief from depression andan increase in intellect has also been observed.

While l-dopa has produced some rather promising results in experimentaltherapy, in some instances it does not show benefits unless used inrelatively large amounts. This causes undesirable side effects such asnausea, vomiting, hypotension and abnormal involuntary movements as wellas mental changes.

It would, therefore, be a significant advance in the art if some meansof potentiating l-dopa were found whereby the resultant new compositioncould be used to effectively treat Parkingsons disease at relatively lowdosage levels, and thus the above unwanted side effects as well asothers are avoided.

SUMMARY OF THE INVENTION It, therefore, becomes an object of theinvention to provide a composition useful in treating Parkinsonism. Aspecific object of the invention is to provide a method of treatingParkinsonism with a drug exhibiting a low level of side effects, if any,and which does not become tolerated over extended usage. Essentially theinvention here is concerned with a composition useful in treatingParkinsons disease, said composition comprising in combination l-dopaand 2-imino-5-phenyl-4- oxazolidinone or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION L-dopa or3-(3,4-dihydroxyphenyl)-L-alanine is, of course, well known, as is2-imino-5-phenyl-4-oxazolidinone. However, it is believed that thecombination is novel as well as their combined use in treatingParkinsonism. It was found here that the oxazolidinone markedlypotentiates the activity of l-dopa as an anti- Parkinsonism drug andthat the combined treatment appears to act in a synergistic manner.

Typical compositions of the invention will be constituted in the ratioof 005-40 parts of oxazolidinone per 1.0 part of l-dopa. More often saidratio is 0.1-2.0 parts oxazolidinone per 1.0 part of l-dopa.

For use in treating Parkinsons disease, the above composition may beadministered in either liquid or solid form. Thus, the active compoundsmay be provided in granulation, tablet, capsule, elixir and other dosageforms. Oral administration is preferred and is the most convenient.Other means of administration may be employed such as, for example, byintraperitoneal or intramuscular injection. The active ingredients canalso be incorporated in an oil or wax base and administered in the formof a suppository.

When administered in a unit dosage form, the active ingredientscomprising l-dopa and oxazolidinone will be present in a total amount of5-100 milligrams, more often 5-50 milligrams accompanied by apharmaceutically acceptable carrier.

The compositions of the invention are found to be effective in humans ata dosage range of from about 0.1 to about 400 mgjkg. of body weightdaily. More often the dose is l-200 mg./kg.

EXAMPLE I One basic approach for evaluation of anti-Parkinson activityis estimating reversal of the extrapyramidal effects of deserpidinewhich depletes biogenic amines in animals and in man, which test wasemployed here.

Specifically, deserpidine was administered to mice 24 hours prior to thetest at a level of 50 mg./kg. The deserpidine was administered orally.

Twenty-four hours after administering the deserpidine, l-dopa was thengiven by intraperitoneal injection at mg./kg. The l-dopa had no effectin reversing the effects of deserpidine. It was given a rating of 0. Inthis test a rating of 0 indicates no effect; a rating of 1 indicatesslight effect; a rating of 2 indicates moderate effect and a rating of 3indicates marked effect or complete reversal.

When a combination treatment involving l-dopa and2-imino-5-phenyl-4-oxazolidinone was employed, definite reversal of thedeserpidine effects were noted. Specifically, the two compounds wereadministered to mice with with the l-dopa dosage being held constant andthe oxazolidinone dosage being varied. Table I shows the results of thistest, and specifically points out the definite potentiation of l-dopa bythe combination with oxazolidinone.

EXAMPLE I! In this series of tests, the compositions of the inventionwere evaluated as to their reversal of deserpidine effects whereinRhesus monkeys were the animals treated here. Eighteen hours prior tothe test the monkeys were given mg./kg. of deserpidine orally. Eighteenhours after this administration, l-dopa was administered alone at alevel of mg./kg. No effect upon deserpidine symptoms was noted with useof l-dopa here.

As in Example I, use of 2-imino-5-phenyl-4-oxazolidinone markedlypotentiates the effects of l-dopa. Specifically, 2 mgjkg. ofoxazolidinone was administered along with 25 mg./kg. of l-dopa. Completereversal of the deserpidine effects was now realized. That is, thesedative effects of deserpidine were completely reversed by use of thecombination of chemicals.

While in the above examples l-dopa and 2-imino-5- phenyl-4-oxazolidinonewere administered separately, it is understood, of course, that the twomaterials may be combined and administered at one time, with thepreferred ratio of the two being as set out above.

It is understood, of course, that in addition to use of 2 the abovesalts or bases in combination with 2-im1no-5- phenyl-4-oxazolidinoneitself, salts of the oxazolidinone compound may also be employed here.

This particular oxazolidinone is a relatively weakv acid, and thereforesalts may be formed via combination with a strong base. For example,alkali metal salts may be formed such as the sodium, lithium, etc.salts. In addition, alkaline earth metal salts such as the calcium saltmay also be formed. Normally, these salts are formed by reacting theoxazolidinone with a strong alkali metal or alkaline earth metal base oranhydride such as sodium hydroxide, potassium hydroxide, lithiumhydroxide, calcium hydroxide etc., or sodium hydride, calcium hydride.

What is claimed is:

l. A method of treating a patient suffering from Parkinsons diseasewhich comprises administering to said patient at least an effectivedosage of'a composition comprising in combination l-dopa and2-imino-5-phenyl-4-oxazolidinone or a salt thereof, said compositionbeing constituted in the ratio of 0.054.0 parts of oxazolidinone orsalt'per 1.0 part of l-dopa.

2. The method of claim 1 wherein said dosage range is from 0.1 to about400 mg./kg. of body weight daily.

3. The method of claim 2 wherein said dosage range is 0.1-200 rug/kg.

4. The method of claim 1 wherein l-dopa is ad- 5 ministered separatelyfrom the administration of oxazolidinone.

2. The method of claim 1 wherein said dosage range is from about 0.1 toabout 400 mg./kg. of body weight daily.
 3. The method of claim 2 whereinsaid dosage range is 0.1-200 mg./kg.
 4. The method of claim 1 wherein1-dopa is administered separately from the administration ofoxazolidinone.